Morphine is administered to patients of widely varying ages. However, little data exist regarding the influence of aging on the disposition or analgesic effect of opiate analgesics. Recent clinical data reveal a reduction in the systemic clearance of morphine during aging, contradicting an earlier study that suggested the pharmaco-kinetics of morphine were age-dependent. The mechanism(s) underlying and age- related decrease in morphine clearance may include decreased metabolic enzyme activity and blood flow in both the liver and kidney, organs which are largely responsible for the biotransformation and elimination of morphine. Furthermore, older adults appear to be more sensitive to the analgesic effects of morphine than their younger counterparts. Changes in the pharmacologic response to morphine with increasing age may be due to altered systemic clearnce of the drug, or may involve a complex relationship between drug penetration to the site of action, opiate receptor number, affinity of the receptor for the ligand, and central nervous system response to nociceotive stimuli. The proposed project will use a comprehensive multiexperimental approach in an effort to determine the factor(s) responsible for age-related changes in response to morphine. The systemic pharmacokinetics of morphine will be examined in Fischer-344 rats (3 to 24 months old) to determine the effects of age on the clearance and distribution volume of morphine. Age-related alterations in the analgesics effect of morphine will be assessed across the target age groups with a tailflick assay. Correlation of analgesic response with blood, brain, and cerebrospinal fluid concentrations of morphine will be determined for each age group. Finally, the effects of aging on invitro receptor binding will be assessed. Parameters obtained in the pharmacokinetic and pharmacodynamic investigations will be incorporated into an integrated kinetic-receptor binding-dynamic model to describe alterations in the disposition of, and response to, morphine during the aging process.